AL amyloidosis is a relatively rare condition, with a worldwide incidence of 5.1–12.8 cases per million population [1,7]. Systemic disease is more common, with localized disease representing just 7–12% of all AL amyloidosis cases [5]. Median age at diagnosis is 64 years with incidence increasing with age; however there is no established association with ethnicity or geography [1]. Pre-existing plasma cell dyscrasias, including MGUS and multiple myeloma, carry a significant risk of progression to AL amyloidosis [10,11]. In 2025, a new definition of light chain MGUS was proposed, with the aim of decreasing the overdiagnosis of monoclonal gammopathies often linked to using the standard reference intervals for serum free light chains (sFLCs) [12]. With the new definition of light chain MGUS based on these revised, more accurate reference intervals, the false-positive rate of free light chain (FLC) testing decreased by 82% [12]. New reference intervals for sFLCs in individuals with chronic kidney disease have been created from the large prospective population-based cohort of the iStopMM study. Using the current reference intervals, 60% and 21% of patients had abnormal kappa and lambda sFLC values, respectively. Novel reference intervals (based on central 99% reference intervals) have been proposed for serum kappa FLC (mg/L), serum lambda FLC (mg/L), and the sFLC ratio in individuals with estimated glomerular filtration rates (eGFR) of 45–59, 30–44, and < 30 mL/min/1.73 m². However, it should be noted that these new ranges were established in a homogeneous cohort; therefore, they may not be fully generalizable to more diverse or wider populations [13]. These updates to the definition of MGUS will directly impact the diagnostic workflow (detection of the monoclonal component) and, in turn, the need for biopsies to detect amyloid deposits [14].

Light chain infiltration leads to multiorgan damage and dysfunction [7]. There are two forms of organ involvement: deposition of insoluble protein leading to organ dysfunction (primarily in the heart and kidneys) and direct tissue toxicity from circulating soluble-free light chains (e.g. elevated N-terminal pro-brain natriuretic peptide [NT-proBNP] values indicative of cardiac stress dissociated from structural alterations) [15]. Symptoms appear after organ damage has already occurred and are related to the organs involved; most patients have multi-organ involvement at the time of diagnosis [7,16,17]. One-year mortality is high (12%–30%), reflecting the failure to diagnose prior to irreversible end organ damage [9,18]. Heart involvement is the major determinant of prognosis and mortality [4,7]. Cardiac dysfunction results from proteotoxicity of the light chains and amyloid deposits that cause widespread disruption of tissue architecture [19].

Advances in treatments of AL amyloidosis in the last 40 years have increased the median overall survival from 1.4 years in the 1980s to 4.6 years in the 2010s, with a growing number of patients achieving survival of ten years or longer [9,20,21]. Improvements in survival have lagged in patients with cardiac involvement. Deaths result from disease-related factors with cardiac failure (32%) and sudden unexpected death (23%) being the leading causes [9]. Overall survival in the 2010s was 8.8 years for patients with no cardiac involvement compared with 2.6 years in patients with cardiac involvement [9]. With improved long-term survival (29% of deaths occurring > 10 years after diagnosis), non-AL amyloidosis-related death has increased from 3% to 16% of the total deaths [9]. However, most patients who survived at least ten years required one or more subsequent lines of therapy [20], and patients continued to experience significant and persistent symptom burden after diagnosis, particularly while on active treatment [22].

AL amyloidosis is a heterogeneous disease with the potential to affect multiple organs, resulting in broad and variable clinical presentations that complicates diagnostic characterization [32]. The diagnosis is delayed as symptoms typically emerge only after organ damage has accumulated to the point of dysfunction. Increased serum FLC levels may be present for at least four years before the onset of clinical manifestations [7,33]. Early symptoms of AL amyloidosis are vague (i.e., neurologic symptoms, fatigue, dizziness, abdominal pain) and may be misattributed by patients and HCPs to other, more common conditions or simply as part of aging [16,34,35]. Once symptoms become more serious, their heterogenous nature may further contribute to misdiagnosis and diagnosis delay [36]. In a retrospective study of patient medical records, patients had a median of five precursor diagnoses within the two years prior to diagnosis [35]. The median time from symptom onset to AL amyloidosis diagnosis is approximately six months to 2.7 years with 50% of patients visiting five or more physicians of different medical specialties before diagnosis [16]. HCPs involved in diagnosis include, but are not limited to, primary care providers, medical internists, cardiologists, nephrologists, neurologists, gastroenterologists and hematologists [34]. Notably, patients with renal involvement often experience a more direct diagnostic pathway and are frequently diagnosed within six months of symptom onset, likely reflecting the routine use of kidney biopsy in patients with proteinuria. In contrast, delayed diagnosis is particularly consequential in patients with cardiac involvement, for whom early recognition is critical to improving outcomes [32].

The clinical presentation of AL amyloidosis depends on organ involvement, most commonly the heart, kidneys, nervous system, soft tissues, and liver [37] (Supplementary Figure 1, Supplementary Table 2). Symptoms more specific to AL amyloidosis are not common and present later in the disease, further complicating diagnosis [4,16,34]. Symptoms that should immediately raise suspicion of possible AL amyloidosis include the involvement of soft tissues with macroglossia, periorbital purpura, submandibular gland swelling, and the shoulder pad sign; however, these highly specific symptoms are rare and occur only in a subset of individuals [37,38]. In the absence of more specific symptoms, physicians should suspect AL amyloidosis when patients present with heart failure with preserved ejection fraction, nephrotic-range proteinuria in the absence of diabetes, peripheral neuropathy, unexplained hepatomegaly, and diarrhea, especially when multiple organ systems are involved [38] (Supplementary Figure 1, Supplementary Table 2).

Assessment for AL amyloidosis is indicated when there is a clinical suspicion of the disease due to the presence of common symptom patterns (Supplementary Figure 1, Supplementary Table 2). Patients with pre-existing conditions that increase the risk of acquiring AL amyloidosis would benefit from regular screening for biomarkers of the disease that may increase before symptoms appear. Biomarkers, including alkaline phosphatase (ALP), proteinuria, and NT-proBNP, should be monitored regularly in patients with MGUS to detect early signs of organ involvement [39]. Patients are assessed for AL amyloidosis using a 4-step algorithm: 1) Screening for clinical suspicion of AL amyloidosis, 2) identification of monoclonal light chains, 3) tissue diagnosis, and 4) typing of tissue employing adequate technologies (Figure 1) [7,8,40]. The presence of plasma cell dyscrasia in patients with suspected AL amyloidosis is determined by the identification of monoclonal light chains by three tests: serum protein immunofixation, urinary immunofixation, and the serum kappa/lambda ratio [4,8]. Because the clonal plasma cell population in AL amyloidosis is often small ( < 10% of total bone marrow cells), protein electrophoresis is frequently negative and therefore usually omitted from the diagnostic algorithm [4,8]. Once a monoclonal component has been detected, the presence of AL amyloidosis requires the identification of amyloid fibrils in a tissue biopsy. This confirmation is based on the demonstration of amorphous tissue material that stains positive with Congo red and exhibits the characteristic apple-green birefringence under polarized light, a critical step to avoid both false-positive and false-negative interpretations in the routine practice [4,41,42]. Congo red is a relatively inexpensive dye with a long shelf-life that rebinds all forms of amyloid [41]. The initial evaluation typically relies on combined sampling of peripheral tissues, such as abdominal fat aspirate or biopsy, bone marrow, or salivary gland, which are more accessible and carry lower procedural risk. However, negative fat and bone marrow biopsies do not rule out AL amyloidosis; there is still an approximate 15% chance of disease and hence further biopsies of the appropriate organs are recommended [18]. Biopsies of clinically affected organs provide higher sensitivity and specificity but are less readily available and associated with a higher risk of complications, such as perioperative bleeding of which kidney biopsies pose a significant risk [4,18,43]. The sensitivity of peripheral tissues in detecting amyloid deposits can be lower in the clinical practice than that demonstrated by the literature (e.g., abdominal fat pad biopsy). In individuals who are highly suspected of having AL amyloidosis and have an absence of amyloid deposits in peripheral tissues, biopsy of an affected organ should be prioritized. According to the American Society of Hematology (ASH) guidelines on the diagnosis of AL amyloidosis, the combination of fat pad sampling and bone marrow biopsy yields a high sensitivity (89%). When performed individually, however, sensitivity is significantly lower (76.6% and 55.1%, respectively), whereas endomyocardial biopsy demonstrates a sensitivity of 93.5%. However, these guidelines recognize that proceeding with one approach over the other is dependent on several external factors including resource access, available expertise, clinical presentation, and associated costs [13]. Once amyloid deposits have been confirmed with Congo red testing, the type of amyloid protein must be identified in a tissue biopsy using more specific methods such as immunological techniques or mass spectrometry. Genetic testing may also contribute to subtyping the amyloidosis in hereditary cases [44]. The choice of the subtyping technique depends on ease of referrals, funding availability, cost, and access to specialized resources, including specific antibodies and mass spectrometry expertise [44].

Figure 1.

Diagnostic algorithm for AL amyloidosis

Adapted from Palladini [4]

AL: Immunoglobin light chain amyloid protein; BNP: B-type natriuretic peptide; ECG: electrocardiogram; EF: Ejection fraction; FLC: Free light chain; MGUS: Monoclonal gammopathy of undetermined significance; NT-proBNP: N-terminal pro-B-type natriuretic peptide.

In the absence of a monoclonal component, patients with suspected cardiac amyloidosis should be tested for transthyretin (ATTR) amyloidosis using cardiac scintigraphy with bone-seeking tracers, notably 99mTc-diphosphono-propanodicarboxylic acid, 99mTc-pyrophosphate, and 99mTc-hydroxymethylene diphosphonate [4,45]. A DNA analysis is necessary to differentiate between hereditary and wild-type ATTR amyloidosis and to dismiss other rarer hereditary forms [4,45].

Patients diagnosed with AL amyloidosis undergo risk stratification and disease staging based on the type and extent of organ involvement to help determine prognosis and guide treatment decisions. Over recent decades, improved diagnostic accuracy and therapeutic advances have led to a better understanding of the natural history of AL amyloidosis and contributed to better overall outcomes [9]. Nevertheless, prognosis remains strongly influenced by the diagnostic timing and the presence and severity of cardiac involvement – a key determinant of both treatment feasibility and survival. Cardiac complications, particularly progressive heart failure and malignant arrhythmias, remain the leading causes of morbidity and mortality in AL amyloidosis [9]. The current staging systems therefore rely heavily on measures of cardiac function and circulating biomarkers of cardiac damage [8,29]. Cardiac biomarkers assessed in these models include levels of troponin T (TnT) and NT-proBNP or brain natriuretic peptide (BNP) [46]. Additional criteria used for disease staging include an assessment of clonal disease based on the difference between involved and uninvolved circulating FLC levels (dFLC); however, in the daratumumab era, this may not be as prognostically important [18]. Cardiac biomarkers alone might be more suitable to stage AL amyloidosis as baseline FLC showed no effect on the depth of response in newly diagnosed patients [47]. A renal staging system, in which renal involvement is assessed as the eGFR level and degree of proteinuria, helps predict the risk of progression to dialysis [46].

Staging models that utilize soluble cardiac biomarkers include the Mayo 2004 model, the European 2015 modification of Mayo 2004 model, the Mayo 2012 model, and the Boston University (BU) model [7,48,49]. The Mayo 2004 model and its European modification rely on TnT and NT-proBNP levels to assign risk and are most widely used to determine patient management, while the Mayo 2012 and BU models incorporate dFLC and BNP, as additional markers of disease burden, respectively [4,7,8,48]. The European modification of Mayo 2004 more accurately predicts early death than Mayo 2012; the Mayo 2012 more accurately predicts late survival than Mayo 2004 [48]. In 2024, Khwaja et al. found that incorporating myocardial global longitudinal strain (GLS) into the European modification of Mayo 2004 allowed the identification of patients at highest risk of death (“Stage IIIc”), though this model has not yet been externally verified [50]. In addition to the cardiac-based models, a renal staging model has been developed to predict the risk of progression to dialysis [8,48] (Supplementary Table 3). Additional biomarkers with predictive qualities that have not yet been incorporated into staging systems include von Willebrand factor, d-dimer, and growth differentiation factor 15 [8,48].

Patients with AL amyloidosis in Brazil face significant diagnostic delays, often consulting multiple HCPs including general practitioners, nephrologists, and cardiologists and at the time of diagnosis they typically present with multi-organ involvement. Early diagnosis of AL amyloidosis is critical to improve outcomes and prevent organ damage. Educational initiatives for patients and HCPs and the establishment of multidisciplinary specialized amyloidosis centers are needed in Brazil to improve the time to diagnosis and subsequent prognosis of patients. In line with recent International Society of Amyloidosis (ISA) recommendations, such centers should be structured to include a multidisciplinary clinical team; adequate infrastructure and access to diagnostic tools; expertise across different amyloidosis subtypes; access to disease-specific therapies; patient support services; research and educational activities; telemedicine capabilities; and integration within collaborative networks [51].

Patients in Brazil often require ≥2 biopsies for the diagnosis of amyloidosis. Improving the timeliness and accuracy of amyloidosis diagnosis requires expanded availability of monoclonal protein screening, prompt access to tissue biopsy, and standardized recommendations for biopsy site selection and timing. Additional training of pathology centers in how to consistently perform Congo red and polarized light testing is required. The use of a multidisciplinary team approach to support biopsies is recommended. Furthermore, standardization is needed for transportation protocols, for laboratory analysis of tissue samples, and for the availability and use of diagnostic tests.

Cardiac involvement in AL amyloidosis is associated with the worst outcome. Cardiac biomarker testing should be used at every stage, including diagnosis, prognostic evaluation, patient follow-up, and assessing suitability for transplantation. Validated models of biomarkers and cut-offs, as well as scoring systems, should be followed to standardize evaluations. Identification and quantification of involved FLC is important for biomarker testing and prognostic classification and response assessment.

A multidisciplinary approach is crucial to support AL amyloidosis patients through the many challenges they experience. The main goal of treatment is to achieve a rapid and deep hematological remission by eliminating or reducing the amyloid-producing clonal cell population [4,52]. A degree of recovery in organ function occurs after circulating FLCs have been significantly reduced; recovery can continue to improve for up to two years after treatment, even when the amount of amyloid deposit remains unchanged [53–56]. Given this, if an adequate hematological response (very good partial response or higher) is achieved, it is recommended to avoid premature therapeutic changes despite a lack of organ response within the first few months. Organ non-response is more common with more advanced disease and when more than one organ is involved [53,54].

Management of AL amyloidosis involves supportive care and plasma cell-targeting therapies derived from multiple myeloma protocols, utilizing a similar risk-adapted approach [52]. The current standard of care for newly diagnosed AL amyloidosis is the quadruplet regimen consisting of daratumumab, bortezomib, cyclophosphamide, and dexamethasone. Approved by the Brazilian Health Regulatory Agency (ANVISA), this is also the only treatment approved by the Food and Drugs Administration (FDA) in the United States [57,58]. Standard treatment for AL amyloidosis from the late 1970s through the early 2000s involved the alkylating agent melphalan initially in combination with the corticosteroid prednisone and later with dexamethasone [59]. While melphalan-dexamethasone continues to be an effective treatment [60], hematological response rates and overall survival improve when bortezomib is added [46,61]. Results of the ANDROMEDA study show that adding daratumumab to the combination of bortezomib-cyclophosphamide-dexamethasone regimen further improved the speed and depth of hematological response, resulting in a clinically meaningful and significant improvement in overall survival and survival free from major organ deterioration [62,63]. An upfront treatment algorithm for AL amyloidosis is shown in Figure 3 [64,65]. In cases where daratumumab is unavailable, the bortezomib-cyclophosphamide-dexamethasone should be used. As mentioned, in Brazil, daratumumab is approved for the treatment of AL amyloidosis, but access is only available to patients with supplementary health assistance [66]. Most patients from public institutions receive bortezomib, cyclophosphamide, melphalan and dexamethasone; the addition of daratumumab, when available, is recommended.

Figure 3.

Therapeutic algorithm for the treatment of AL amyloidosis*

*In cases where daratumumab is unavailable, the bortezomib-cyclophosphamide-dexamethasone should be chosen.

ASCT: Autologous stem cell transplant; BMDex: Bortezomib, melphalan, and dexamethasone; CR: Complete response; CyBorD: Cyclophosphamide, bortezomib, dexamethasone; Dara: Daratumumab; eGFR: Estimated glomerular filtration rate; MDex: Melphalan and dexamethasone; Mel140: melphalan 140 mg/m²; OR: Organ response; VGPR: Very good partial response.

Due to the high risk of mortality, ASCT is generally restricted to younger individuals with limited cardiac involvement, although evidence is lacking for its superiority over chemotherapy alone [57,67]. Indeed, only a small proportion of patients (around 20%) with AL amyloidosis are eligible for ASCT [4]. Furthermore, major shifts in ASCT utilization have occurred since the introduction of daratumumab, with some centers experiencing an 80% decline in treatment volume [68]. The decision to use ASCT should be approached with caution and should take into account the patient’s condition and the experience of the centers. Patient selection for ASCT should ideally follow risk-adapted recommendations, such as the European Hematology Association–International Society of Amyloidosis (EHA-ISA) guidelines for stem cell transplantation in systemic AL amyloidosis [69]. ASCT should not be offered to patients with: advanced cardiac involvement (particularly Stage IIIb disease), medically refractory pleural effusions, refractory orthostatic hypotension, active gastrointestinal bleeding, or acquired factor X deficiency with active bleeding. Conditioning melphalan should be dose-adjusted (200 mg/m² or 140 mg/m²) according to age, cardiac status, renal function, and overall condition. Similarly stringent eligibility criteria have been published by the Mayo Clinic [32]. Solid organ transplantation may be an option for patients with more advanced disease, particularly with renal involvement, but again this is not well supported by available data [70,71]. Use of immunomodulatory drugs, such as lenalidomide, or proteasome inhibitors (e.g., carfilzomib, ixazomib) alone or in combination is limited, due to the increased potential for cardiotoxicity and lack of evidence of efficacy [26]. Agents that directly target fibril formation and amyloid deposits at early stages of clinical development [72] are not currently available for clinical use. Although Phase 3 studies have been conducted for anti-amyloid agents such as birtamimab and anselamimab, these trials did not meet their primary endpoints [73,74].

Regarding second-line treatment, daratumumab rechallenge can be considered, with bortezomib re-exposure also being an option in certain circumstances. Patients who achieve a durable, well-tolerated response to a bortezomib-containing regimen, particularly in the absence of neuropathy, may be considered for proteasome inhibitor re-exposure, ideally employing a different combination. For patients who have not previously received anti-CD38 therapy, daratumumab-based regimens represent a reasonable option [75]. Also, enrollment in clinical trials should be encouraged if feasible [76,77]. While not currently FDA approved, venetoclax is an investigational second-line treatment option for patients with AL amyloidosis with the t(11;14) translocation [78]. Venetoclax has demonstrated good efficacy in patients with relapsed or refractory AL amyloidosis harboring the t(11;14), although its availability remains largely restricted to clinical trials [78,79]. In a multicenter, retrospective analysis of 22 patients with AL amyloidosis treated with venetoclax, the median number of prior lines of therapy was one (range: 1–3). The most common frontline regimen was daratumumab, bortezomib, cyclophosphamide, and dexamethasone (68%), with 22% of patients having previously undergone ASCT. All 22 patients achieved a complete response or very good partial response with venetoclax, though nine patients eventually progressed before or after venetoclax discontinuation [80].

Response to therapy is assessed in terms of hematological response and organ-specific responses, with cardiac involvement being the most important factor in early mortality [46]. Hematological response is measured as the difference between involved and uninvolved free light chains (dFLC) [26,46] and organ response is assessed by measuring organ-specific biomarkers [26,46]. Supplementary Table 4 summarizes the criteria for evaluating hematologic response and organ response to therapy [48]. A significant decrease in dFLC is associated with improved clinical outcomes; specifically, achieving a dFLC < 10 mg/L predicts superior overall survival, higher organ response rates, and a longer time to next treatment [26,46]. Assessment of hematological response should be conducted at least every three months while on active treatment and after completion of treatment; proper monitoring should begin early, especially in the initial treatment phase [26]. As rising dFLC levels per se do not uniformly mandate the initiation of second-line therapy, an individualized approach is needed; some patients may experience prolonged periods without organ progression after hematologic relapse. In a Mayo Clinic study, 23% of patients had no evidence of organ disease progression for a median of 14 months and up to 8.3 years [81]. However, the optimal timing of treatment at relapse remains an area of active debate. Some experts advocate earlier intervention to prevent organ damage [82]. Accordingly, more recent consensus recommendations suggest that, in patients who previously achieved a very good partial response defined as the dFLC < 40 mg/L or better, salvage therapy should be considered in the presence of rising dFLC levels before overt organ progression develops, even if hematologic progression is not seen [32].

In cases of relapsed and refractory AL amyloidosis, treatment options are highly individualized with no universally accepted treatment sequence. While some patients experience slow biochemical relapse without immediate organ deterioration, management must be tailored to prior organ involvement, patient frailty, and the kinetics of light-chain progression. This is best captured by the concept of ‘high-risk dFLC progression’ (dFLC > 20 mg/L, representing > 20% of the baseline and a > 50% increase from the nadir) [83]. Such a personalized strategy is preferred over a uniform ‘watch and wait’ approach. Guidelines developed by the EHA-ISA working group emphasize balancing early treatment to prevent serious organ damage, particularly in patients with significant cardiac, renal, or autonomic involvement, against the risks of premature re-initiation of chemotherapy in frail patients, underscoring the need for individualized clinical judgment [84]. While the optimal sequencing of therapies in relapsed or refractory AL amyloidosis cannot be prescriptive, treatment decisions should be guided by the depth and duration of the initial hematologic response, prior exposure to specific drug classes, and the constraints related to the patient’s condition and the extent of end-organ involvement.

Localized AL amyloidosis accounts for around 10% of all amyloidosis cases [87]. In the clinical practice, localized AL amyloidosis may be misdiagnosed as systemic AL amyloidosis, leading to chemotherapy treatment that is not clinically indicated. Correct staging and diagnosis are therefore essential to avoid intensive treatment for what is often a curable condition. Localized AL amyloidosis presentation is variable, depending on the specific organ involved [88]. Diagnosis of localized AL amyloidosis differs from the systemic form in that it only requires detection of amyloid deposits and identification of the amyloid protein. An initial hematologic evaluation for a monoclonal protein is typically sufficient to rule out systemic AL amyloidosis [88]. In localized AL amyloidosis, there is typically no evidence of a circulating monoclonal protein or systemic organ involvement. Consequently, these patients must be accurately distinguished from those with systemic disease to ensure they receive an appropriate site-specific therapy.

Management of localized disease can be challenging [89]. The goal of treatment for patients is symptom control [88]. Surgical resection is the most common first-line treatment [88,89], while radiotherapy can stabilize refractory and locally advanced disease that is not suitable for surgery. In some cases, a watch and wait strategy may be appropriate. Localized AL amyloidosis usually does not progress to systemic AL amyloidosis [90], which should directly impact how clinical and laboratory follow-up is performed in practice [91].